Doi:10.1016/s0094-0143(02)00192-

Nancy B. Davis, MDa, Ashesh B. Jani, MDb, aDepartment of Medicine, Section of Hematology/Oncology, The University of Chicago Medical Center, 5841 South Maryland Avenue, MC2115, Chicago, IL 60637, USA bDepartment of Radiation and Cellular Oncology, The University of Chicago Medical Center, 5841 South Maryland Avenue, MC 9006, Chicago, IL 60637, USA cThe Ben May Institute for Cancer Research, The University of Chicago Cancer Research Center, 5841 South Maryland Avenue, MC 1140, Chicago, IL 60637, USA Because of the widespread use of prostate- Additionally, the PSA doubling time (PSADT) specific antigen (PSA) for screening, most prostate at the time of biochemical failure, with a cut- cancers are now being detected in a localized stage; off PSADT of less than 10 months, predicts for therefore, most of the 190,000 men destined to be the early development of distant metastasis and is diagnosed with prostate cancer in 2002 are able to predictive of death from prostate cancer [5,6].
undergo therapy with curative intent [1]. Parallel Biochemical failure is defined differently after with screening efforts have been efforts both in the prostatectomy than after radiotherapy and gener- surgery and radiotherapy arenas in technically ally predates clinical failure by about 5 years. The improving treatment. Specifically, bilateral nerve- failure rate–biochemical or clinical–increases, of sparing prostatectomy has improved the quality of course, with advancing stage of disease. Following life of surgery patients, and technical advances in radical prostatectomy, 27% to 53% of men will external beam radiation treatment (EBRT) plan- experience biochemical (PSA only) failure within ning (particularly intensity-modulated radiother- 10 years [5,7]. Biochemical relapse has been dem- apy) and in low-dose rate (LDR) and high-dose rate onstrated to be the single most sensitive sign of (HDR) brachytherapy have allowed many options treatment failure and probably identifies patients to become available for treatment of early-stage who fail to achieve eradication of disease years prostate cancer. Such advances have allowed ex- before clinically apparent recurrences [6]. Early use cellent biochemical control rates for early-stage of hormonal therapy, although widespread, has not disease. Recurrence of prostate cancer remains necessarily translated into increased survival [8].
a significant problem, however, with only 40% of Choice of therapy following failed radical pros- patients being disease-free at 15 years [2]. Pre- tatectomy includes EBRT or a variety of hormonal operative PSA levels of 10 or higher, positive sur- manipulations. Therapies available for patients gical margins, a Gleason score of 8 or higher, and who have failed EBRT include salvage prostatec- seminal vesicle (SV) invasion [3] are predictors of tomy, brachytherapy, cryosurgery, and hormonal biochemical and clinical failures following either manipulation [6,9,10]. This article presents a gener- radical prostatectomy or radiation therapy [4].
al review of secondary therapy, both local andsystemic, with a synopsis of the current data. Figure1 shows the suggested clinical flow for patientsrelapsing after primary therapy for localized * Corresponding author. University of Chicago Cancer Research Center, 5841 South Maryland Avenue, E-mail address: [email protected] 0094-0143/03/$ - see front matter Ó 2003, Elsevier Science (USA). All rights reserved.
doi:10.1016/S0094-0143(02)00192-1 N.B. Davis et al / Urol Clin N Am 30 (2003) 403–414 N.B. Davis et al / Urol Clin N Am 30 (2003) 403–414 nature of a recurrence as well as in defining thetumor bed target for radiotherapy.
The decision to undertake a prostatectomy is The role of hormones in addition to or in- based primarily on patient age, stage of disease, dependent of adjuvant radiotherapy is discussed pretreatment PSA, and Gleason score. Although the pathologist can provide accurate informationabout the status of margins, extracapsular exten-sion (ECE), SV invasion, and perineural or lymph- ovascular invasion, there is not yet a well-developed consensus on the criteria for offering immediateadjuvant radiotherapy [11]. Focal margin positivity External beam radiotherapy requires periodic or ECE are not, generally speaking, strong enough follow up by digital rectal examination (DRE) to warrant immediate radiotherapy, but diffuse and PSA. Biochemical failure usually predates margin positivity, SV invasion, or ECE generally are.
clinical failure, especially in the T1c patient pop- ulation. Because a PSA bounce phenomenon can nadir that is undetectable as opposed to a nadir be inherent in any treatment modality that does that remains detectable postoperatively. An un- not completely remove the prostate, well-devel- detectable postoperative nadir, with a subsequent oped criteria by the ASTRO consensus panel rise to a detectable value, is more strongly in- [21,22] recommend that biochemical failure be dicative of a local-only recurrence amenable to declared only after three successive rises from the salvage by local radiotherapy. A PSA concen- nadir. The consensus panel warns that declaration tration that is persistently detectable after prosta- of biochemical failure serves primarily as an tectomy, unless the source is apparently grossly endpoint for clinical trials and not necessarily positive margins, speaks strongly for undetectable for clinical intervention. Furthermore, a different metastases, and cure for such patients is unlikely ASTRO consensus panel [18] did not recommend with treatment directed at only the pelvis. In routine prostate bed biopsy for rising PSA after addition to post-prostatectomy PSA value and velocity [12], grade (GS ‡ 7), SV involvement, and Nonetheless, the clinician must often decide, PSA recurrence within 2 years of prostatectomy based on the parameters previously discussed, [13] have been found to be prognostic for reduced whether to use local therapy after biochemical efficacy of local-only salvage therapy.
or clinical failure [23–25]. The local treatment op- Although retrospective reviews of the role of tions after EBRT are prostatectomy, cryotherapy, immediate or delayed adjuvant therapy report freedom from failure rates at 3 years of 20% to Prostatectomy can be technically challenging as 65% [14–17], results of post-prostatectomy radio- first-line therapy but becomes more so after pre- therapy treatment have not yet been reported vious radiotherapy. The fibrosis in the prostate and in the randomized setting. Ongoing European periprostatic tissue frequently results in inconti- Organization for Research and Treatment of nence following salvage prostatectomy. This qual- Cancer (EORTC), National Cancer Institute ity-of-life issue, taken in context with the increased age of the patients, means that only a few patients (CALGB) studies are still examining this impor- failing EBRT opt for salvage prostatectomy.
tant clinical question. If adjuvant EBRT is given, Nonetheless, the CALGB has an ongoing salvage a consensus statement by the American Society of prostatectomy trial, and the final analysis of this Therapeutic Radiology and Oncology (ASTRO) trial should cast more light on the morbidity and [18] recommends a dose of 64 Gy or slightly outcome of post-EBRT salvage prostatectomy. In higher to the prostate bed. This dose level is the meantime, smaller studies [26–32] have reported considered tumoricidal and yet tolerable to tissue techniques that are encouraging with regard to im- surrounding the prostate bed. ProstaScintÒ (Cy- proving outcome (long-term disease-free survival togen Corp, Princeton, NJ) [19,20] a nuclear rates of 30%–40%) while minimizing morbidity.
medicine scan using technetium-labeled anti- Similar to prostatectomy, salvage brachyther- PSMA directed at the intracellular portion of apy poses morbidity concerns. Although many the PSMA protein, which has increased yield providers decline this form of salvage therapy when the PSA concentration is greater than 0.25 because of morbidity concerns, the dose that can ng/dL, may assist in determining the local-only be given by brachytherapy is by its nature more N.B. Davis et al / Urol Clin N Am 30 (2003) 403–414 focused within the prostate. Small, single-institu- radical prostatectomy [40,41]. Increasing use of tion studies [33,34] have reported biochemical salvage brachytherapy is being reported [42].
control rates ranging from 25% to 70% at 5 years Androgen ablation, however, is effective in treat- ing both local and distant relapse but is gener- Cryotherapy salvage after EBRT failure has ally viewed as palliative, whereas postoperative been reported [35–38]. Although the likelihood of radiation therapy has potential to eradicate local success with EBRT salvage for initial cryotherapy disease [24,40,41]. Androgen deprivation may failure is high, the reported biochemical control be achieved by bilateral orchiectomy, estrogen rates with cryotherapy after EBRT failure are therapy, luteinizing hormone-releasing hormone somewhat lower (20%–50% at 2 years), with (LHRH) analogue therapy, antiandrogen therapy, acceptable morbidity in the reported series.
and combined androgen blockade (CAB).
Immediate versus delayed hormonal therapy Brachytherapy has undergone a revolution in technique and has been shown to have biochemical Both the timing and form of androgen ablation control results for early-stage disease that are are controversial, with no evidence that early roughly equivalent with prostatectomy and EBRT.
hormonal intervention improves survival in PSA- Because of the more extensive experience with LDR only relapse [13,42], although in node-positive brachytherapy over HDR brachytherapy, both as patients early hormone therapy does improve initial therapy and as salvage, this discussion is survival [43]. The only absolute indication for treatment of patients with recurrence following The indications for immediate adjuvant local primary curative therapy is symptomatic metas- therapy for brachytherapy failure are limited to tatic disease [41]. Relative indications for early those unusual situations when the quality of the hormone therapy include radiographic evidence of implant, using well-established dosimetric end- disease progression, a rapid PSADT, and patient points, is inferior enough to warrant immediate preference. Early studies (Veterans Administration EBRT. The much more common situation with Cooperative Urological Research Group (VA- brachytherapy, as with EBRT, is delayed bio- CURG 1 and 2)) suggested that delaying hormonal chemical or clinical failure. Although the ASTRO therapy did not adversely effect survival [44], al- consensus panel definition of biochemical failure was designed primarily for determining PSA failure advantage to early therapy for metastatic disease after EBRT, it has been applied with some success [43,45,46]. Additionally, in a patterns-of-care study to brachytherapy failure. Because of morbidity of patients with a PSADT of less than 12 months concerns by providers about adding a course of following EBRT failure, early hormonal manipu- curative EBRT or cryotherapy to a prostate already lation was associated with a significant increase in treated with brachytherapy, the primary local freedom from disease progression at 5 years when salvage option after brachytherapy local failure compared with observation; no such difference was has been declared is radical prostatectomy.
seen in patients with a PSADT greater than 12 Even the prostatectomy literature in this months [6]. In general, men with localized disease regard is scant. Results for salvage prostatectomy who fail after radical prostatectomy will have after initial LDR brachytherapy organ-confined a median time to progression of 8 years after recurrence have been demonstrated to be poor biochemical relapse before development of meta- static disease [5] and a median survival time of 12 to13 years [40]. Application of androgen deprivationtherapy at the time of PSA progression will prolong Systemic therapy for either prostatectomy or time to disease progression but also will expose patients to adverse effects for excessive timeperiods. Deferred endocrine manipulation remains a reasonable option for elderly, asymptomatic men Androgen deprivation is used as frequently as with localized disease as well as for those who radiation therapy after failure of primary radical cannot tolerate prolonged hormonal therapy [47]; prostatectomy; in contrast, 90% of patients failing however, these and other patients who choose to EBRT will undergo hormonal treatment, with defer treatment should be prepared to undergo small numbers of patients undergoing salvage N.B. Davis et al / Urol Clin N Am 30 (2003) 403–414 does not incur a risk of cardiovascular toxicity[50]. For these reasons, LHRH agonists are a Estrogens provide negative feedback to the preferred form of therapy for most patients and hypothalamus and decrease the release of LHRH, thereby suppressing anterior pituitary gland release Impotence and hot flashes are similar to those of luteinizing hormone (LH). Because testicular seen with estrogen therapy. The latter may be Leydig’s cells rely on LH stimulation to produce particularly troublesome, and although no med- testosterone, suppression of LH results in cessation ical therapy has consistently prevented or allevi- of testicular testosterone production. In addition, ated the problem, megestrol acetate, cyproterone estrogen may have a direct effect on prostate cancer acetate, clonidine, the antidepressant venlafexine cells [48]. Achieving castration levels of testoster- (EffexorÒ, Wyeth, Madison, NJ), and a belladon- one may take 1 to 2 weeks following initiation of na-phenobarbitol-ergotamine preparation (Beller- galÒ, Novartis Pharmaceuticals, East Hanover, The optimal dosage of estrogen therapy has not NJ) have all been used with varying success and been established. Oral diethylstilbestrol (DES) at may be tried for the patient with unacceptable 3 mg/day results in castration levels of serum testosterone, whereas doses of 1 mg/day inconsis- Initial randomized trials of LHRH agonist tently lower serum testosterone and doses less than compared 1 mg subcutaneous leuprolide (Lu- 1 mg/day are not effective [49]. Higher doses of pronÒ, Tap Pharmaceuticals, St. Louis, MO) DES, such as the 5 mg/day used in the oft-cited with 3 mg/day oral DES, revealing no statistically Veterans Administration (VA) trials, were associ- significant difference in efficacy but excess cardio- ated with an increased incidence of fatal cardio- vascular toxicity with DES [51]. Subsequently, vascular events [48]. Serious side effects of estrogen a series of trials compared goserelin acetate therapy include myocardial infarction, cerebrovas- (ZoladexÒ, Astra-Zeneca, Wilmigton, DE) with cular accident, and pulmonary embolus. Other side orchiectomy in patients with advanced prostate effects are attributable to loss of testosterone and cancer and found no difference in efficacy. Leu- include loss of libido, impotence, lethargy, gyneco- prolide availability in depot formulation enabled mastia, and nipple tenderness. Conjugated estro- maintenance of castration levels of testosterone gens, ethinyl estradiol, and medroxyprogesterone for up to 5 weeks with a single injection and acetate have been used unsuccessfully in an effort prompted the US Food and Drug Administration to decrease side effects. Estrogen use has dimin- (FDA) approval of this formulation for adminis- ished in prostate cancer patients because of the high tration every 4 weeks in 1989. The FDA granted incidence of cardiovascular complications as well approval for depot goserelin acetate in 1991.
as the availability of more convenient therapies.
Leuprolide and goserelin acetate are equallyeffective in suppressing LH and FSH productionand are available in various strengths for admin- Luteinizing hormone-releasing hormone agonists istration every 1 to 4 months, increasing conve- nience and patient compliance. Three other more potent and act by abolishing the pulsatile LHRH analogues exist: buserelin (SuprefactÒ, effects of endogenous LHRH. After an initial, Arentis, Portugal), used extensively in Europe, transient release of LH and follicle-stimulating nafarelin acetate (SynarelÒ, Searle, Chicago, IL), hormone (FSH), both number and function of approved in the United States for gynecologic use LHRH receptors on pituitary gonadotropin cells and seldom used for prostate cancer and triptor- decline rapidly. Ultimately, minimal to no LH elin pamoate (TrelstarÒ, Pharmacia Oncology, and FSH release occurs, and there is a conse- Kalamazoo, MI), recently FDA approved for quent rapid decrease of testicular testosterone advanced prostate cancer as either a 1 month production [48]. The initial stimulation of LH and (3.75 mg) or 3 month (11.25 mg) injectable FSH release causes a surge in testosterone pro- duction and may transiently worsen pre-existing Investigations of new delivery methods for bone pain or urethral obstruction. This effect LHRH agonists are ongoing. The ViadurÒ system lasts approximately 1 week before the decline of (Bayer Corp, West Haven, CT) is a subcutaneous LHRH receptors, and symptoms should be man- osmotic pump that delivers leuprolide minidoses aged expectantly. The use of LHRH agonists com- for up to 1 year. Implantation of the titanium pares favorably with orchiectomy but, unlike DES, cylinder is performed with a short trocar in the N.B. Davis et al / Urol Clin N Am 30 (2003) 403–414 upper arm between the biceps and triceps; re- seen with estrogen use and also include a low moval and replacement are likewise easy pro- incidence of stimulation of the cancer [53].
cedures. Other designs (eg, AbarelixÒ, Praecis Therefore, these agents are uncommonly used.
Pharmaceuticals, Waltham, MA.) include novel Megestrol acetate is primarily used as an anti- amino acid substitutions in the LHRH deca- cachectic agent in the setting of cancer, and CPA peptide that immediately suppress androgen pro- is used in Europe as part of maximal or CAB.
duction, thus bypassing the initial surge of Neither agent used alone completely suppresses testosterone seen with traditional LHRH agonists.
testosterone production; additionally, tachyphy-laxis may develop, with testosterone levels return- Bilateral orchiectomy removes approximately 90% of circulating testosterone, decreases serum Nonsteroidal antiandrogens are used in CAB PSA concentration, and improves symptomatic but may also be effective as monotherapy. Three bone pain. The low cost, simplicity, lack of agents, flutamide (EulexinÒ, Schering-Plough, compliance issues, and immediate decrease in cir- culating testosterone make orchiectomy a prac- Aventis Pharmaceuticals, Bridgewater, NJ) and tical alternative. Although generally safe and bicalutamide (CasodexÒ, Astra-Zeneca, Wilming- performed on an outpatient basis under local anes- ton, DE), are currently available. Although thesia with low morbidity, surgery still poses a flutamide has a relatively short half-life necessi- small risk of hemorrhage and infection. Subcapsu- tating frequent oral dosing, both nilutamide and lar orchiectomy, in which the tunica albuguinea bicalutamide are given once daily. Because there is and epididymis of each testis are left intact, has no decrease in LH production, testosterone levels been criticized for possibly leaving functional may be normal or slightly increased, and potency testicular tissue intact as well. Postoperative may be spared. The most common side effects are hormonal assays, however, show this risk to be diarrhea, nausea, and vomiting. Rare adverse negligible [48]. The only major drawback to events include hepatotoxicity with flutamide, orchiectomy is the psychologic trauma of removal pulmonary fibrosis with bicalutamide, and de- of the testes; a subset of men will not consider creased adaptation to darkness with nilutamide.
orchiectomy, and for these patients medical cas- Some non–cross-resistance exists between first-, second-, and third-generation antiandrogens de- spite a similar mechanism of action. Scher et al [52]used bicalutamide to treat 51 patients with tumor Antiandrogens bind to androgen receptors in progression after primary androgen ablation and the cytoplasm of target cells and prevent activa- found a response rate of 24%, with 38% of re- tion of many androgen responsive genes. Alter- sponders having previously been treated with flut- natively, anti-androgens may stimulate activation amide. Another study evaluated 31 patients treated of androgen-withdrawal genes. Classically inhib- with bicalutamide; the response rate of 23% in- iting binding of dihydrotestosterone (DHT) and cluded 6 men previously treated with flutamide [54].
testosterone, antiandrogens may be used as mono- Similar responses to nilutamide following fluta- therapy [52] but primarily are used in combina- mide and bicalutamide therapy are reported, al- tion with an LHRH agonist for maximal androgen though no reports exist of responses to flutamide blockade. There are two types of anti-androgens: following bicalutamide or nilutamide therapy.
steroidal, which mimic the progesterone molecule,and nonsteroidal.
Because the mechanism of antiandrogens is to Steroidal antiandrogens include cyproterone inhibit binding of testosterone and DHT to both acetate (CPA) and megestrol acetate (MegaceÒ, peripheral and central androgen receptors, mono- Bristal-Myers Squibb, Princeton, NJ). Both block therapy should be as effective as castration, androgen binding to receptors in target tissues, although there remains a risk of overcoming this possess progestational activity, which indepen- inhibition by testosterone, which may be present dently decreases LH production, and have low in supranormal levels [41]. Evidence exists for levels of androgenic activity. Side effects, includ- decreases in PSA concentration and objective ing cardiovascular morbidity, are similar to those responses for both flutamide and bicalutamide N.B. Davis et al / Urol Clin N Am 30 (2003) 403–414 monotherapy in both androgen-dependent and androgen-independent advanced prostate cancer [52], although the latter has been more extensively androgen is derived from the adrenal gland, and studied. Most studies show bicalutamide to be a higher proportion of androgen within prostate inferior to either medical or surgical castration [41] cancer cells may be of adrenal origin. The two but document a significant quality-of-life advan- most commonly used nonclassic antiandrogens tage to bicalutamide monotherapy in terms of are ketoconazole (NizoralÒ, Janssen Pharmaceu- sexual interest and overall physical capacity [55].
conjunction with corticosteroid replacement doses Staten, NJ) is a 5-alpha reductase inhibitor that to block adrenal androgen production. Ketoco- blocks conversion of testosterone to DHT.
nazole is an antifungal that interferes with Commonly used for benign prostatic hypertro- cytochrome (CYP) 3A4 and inhibits steroidogen- phy, there is interest in finasteride use for esis in both the testes and adrenal glands, resulting prevention of prostate cancer. The results of an in castration-range androgen levels within 24 ongoing 7-year, double-blind, intergroup trial of hours. Most studies of ketoconazole report PSA finasteride versus placebo for the prevention of prostate cancer are eagerly awaited. There is also patients. The precise dose necessary to induce some evidence of activity in metastatic prostate a PSA decline is unclear, but most studies use cancer. A small, double-blind, placebo-controlled a dose of 400 mg three times/day. Long-term trial in men with hormone-sensitive prostate can- patient compliance is poor because of cost, cer found a distinct delay in time to PSA progres- difficulty of administration, and the side-effect sion with finasteride, although not approaching profile which includes nausea and vomiting, pru- that seen with castration in other studies [41].
ritus, nail dystrophy, impotence in some cases, Additionally, androgen ablation was still effective and adrenal crisis, which can be averted by after treatment with finasteride in this popula- concomitant administration of hydrocortisone.
tion. No phase III data support the use of fina- Aminoglutethimide blocks adrenocorticoid syn- steride as initial monotherapy; however, use in thesis by inhibiting conversion of cholesterol to combination with an antiandrogen (flutamide) pregnenolone, a precursor to both cortisol and may be a potency-sparing alternative to tradi- aldosterone. Studies have primarily been in the tional therapy in patients with metastatic disease hormone-refractory metastatic population. Both agents are typically reserved for second-linehormonal therapy after LHRH agonist or CABfailure.
responses in patients with tumor progression Hydrocortisone, prednisone, and dexametha- while undergoing treatment with primary andro- sone have documented activity in prostate cancer gen ablation. Reasons for these responses are and can be used as a third-line hormonal therapy.
multifactorial and include further reduction in Studies of hormone-refractory prostate cancer testosterone production, blockade of the residual patients given steroids versus steroids plus che- serum androgens through binding of the androgen motherapy (mitoxantrone) demonstrated response receptors, reduction in adrenal androgen pro- rates of 22% in patients in the steroid-only arm.
duction, and binding to other nuclear receptors, Once a patient fails an LHRH agonist, anti- such as the alpha or beta estrogen receptor, in the androgen and antiandrogen withdrawal, and prostate cancer cells. It is also clear that testos- second-line therapy with ketoconazole, reason- terone can still stimulate prostate cancer cell able options include chemotherapy, participation growth, even in most hormone-resistant cases.
in a clinical trial. or palliative care. Treatment For this reason, continued testosterone depletion considerations should include the patient’s per- is recommended in all clinical trials of secondary N.B. Davis et al / Urol Clin N Am 30 (2003) 403–414 level [65]. Phase II studies have found this therapyto be well tolerated and to improve quality of life [44,64]. Patients can be maintained off androgen androgen in combination with either an LHRH deprivation therapy for prolonged periods of time agonist or orchiectomy to eliminate testicular and without disadvantages in either time to progression adrenal androgen production simultaneously and or survival [63,65]. This approach is still undergo- completely and was shown in animal models to ing phase II testing and should be considered enhance antitumor effects [58]. Although a more investigational until survival data are mature.
rapid and pronounced response may be seen withcombination therapy, this response may not trans- late into an advantage in either survival or time toprogression [40]. Numerous randomized studies have been conducted to evaluate the effects of CAB antiandrogen therapy while maintaining testoster- and have used various primary androgen depriva- one suppression may be associated with a bio- tion techniques with various forms of antiandrogen chemical response in up to 20% of patients [66] and, therapy, with conflicting results. Comparisons of in some cases, with symptomatic and objective castration plus cyproterone, DES [59], or flutamide responses. The mechanism for this response is [58] versus castration alone have failed to show unknown. Mutated androgen receptors, seen al- a benefit of CAB in terms of overall or progression- most exclusively in tumors treated with CAB and free survival. The most recent meta-analysis stimulated by binding of antiandrogens, have been suggested a statistically significant survival advan- ruled out as a general explanation for this pheno- tage in using CAB with the non-steroidal agents menon [67]. Because antiandrogen withdrawal is (flutamide and nilutamide). In contrast, the use of required for enrollment in clinical trials, and this a steroidal agent (cyproterone acetate) was associ- potential benefit exists, it is reasonable to initiate ated with a decreased survival. Conflicting studies, withdrawal for patients with progressive disease evaluating LHRH agonist therapy with or without receiving antiandrogen therapy. Withdrawal re- antiandrogen therapy [60], LHRH agonist plus sponses occur in approximately 10% to 30% of antiandrogen therapy versus castration alone [61], patients [44], and the likelihood of response may and castration with or without nilutamide [62], correlate with duration of exposure to the anti- showed a benefit to CAB. Additionally, compari- androgen. Responses will generally be observed son of LHRH agonist plus flutamide versus within a few weeks after withdrawal, although bicalutamide revealed a benefit in time to pro- responses to bicalutamide withdrawal may occur gression for LHRH agonist plus bicalutamide [25].
later, possibly because of the longer half-life. The Currently, CAB should be considered for palliation duration of response is typically 3 to 4 months but in symptomatic, advanced prostate cancer.
does not usually last more than 6 months.
The concept of intermittent hormonal therapy is based on the hypothesis that prolonged androgendeprivation therapy may stimulate progression Salvage surgery, cryotherapy, and hormonal from androgen-dependent to androgen-indepen- deprivation are options for the patients who have dent prostate cancer [63,64] Periodic reintroduc- failed primary radiation therapy for prostate tion of endogenous androgen after androgen cancer. Although salvage surgery has been shown withdrawal may result in generation of differenti- to lead to long-term disease-free survival [68], ated tumor cells and therefore may delay emergence associated morbidity (eg, incontinence) and high of the androgen-independent phenotype [44,64].
recurrence rates have prevented wide acceptance.
Preclinical evidence exists in some cell lines Use of androgen deprivation as neoadjuvant (LNCaP, Shionogi), but not in others (Dunning) therapy with salvage surgery for clinically localized [65]. Clinically, intermittent hormonal therapy recurrent prostate cancer has been studied by consists of androgen deprivation continued for Garzotto et al [68] in 29 men with locally recurrent some time following adequate testosterone sup- prostate cancer following primary radiation ther- pression. Following discontinuation of hormone apy. They used either surgical or medical castration therapy, resumption is determined by PSA progres- for 3 months preoperatively, followed by salvage sion, usually caused by a recovering testosterone surgery, and continued androgen deprivation post- N.B. Davis et al / Urol Clin N Am 30 (2003) 403–414 operatively indefinitely in patients with T3 or T4 or overall survival, disease-specific survival, or free- node-positive disease. For those responding to dom from local relapse were evident. The addition androgen ablation preoperatively, there was a de- of androgen deprivation to EBRT has been shown creased incidence of surgical margin involvement, to improve both disease-free and overall survival correlating with improved disease-free (79%) and rates for men with locally advanced prostate can- disease-specific (92%) survival at 5.7 years. The cer. The optimal timing and duration of hormone 5 patients who did not respond to preoperative manipulation is still undefined, and whether androgen ablative therapy had a low disease- early hormonal therapy as a single method is as specific survival rate (20%), a higher rate of positive effective as radical prostatectomy, radiation ther- surgical margins, and perhaps should not be apy, or combined-modality therapy for locally ad- considered candidates for salvage surgery [68].
vanced prostate cancer remains to be answered [4].
The effect of EBRT on locally recurrent disease Eventually, prostate cancer becomes hormone following radical prostatectomy has been con- refractory, and the treatments discussed previously firmed in several studies, and generally 30% to will cease to be of use. Median survival time 60% of patients will revert to an undetectable following development of hormone-resistant pros- PSA concentration following salvage radiation tate cancer is 12 to 15 months. Survival is likely to therapy [42]. Responses correlate to preoperative be longer in those with biochemical failure only PSA concentration, pathologic features of the [69]. Primary androgen deprivation with an LHRH primary tumor, the absolute PSA concentration at agonist should continue for the life of the patient to the time of salvage radiation (PSA < 1.0 being prevent testosterone production with a concomi- best), and the timing of PSA recurrence, with men tant worsening of disease symptoms. If the patient whose PSA concentration increased more than 1 maintains a good performance status following year following surgery maintaining undetectable antiandrogen withdrawal and any second- or third- levels more often than those whose PSA concen- line hormonal therapies, treatment with either tration increased earlier. Studies evaluating radi- standard chemotherapy or on a clinical trial is ation therapy versus combined radiation plus reasonable. For patients with poor performance hormone manipulation for locally advanced status and for elderly patients who are asymptom- prostate cancer are difficult to interpret; adding atic, palliative care is reasonable.
hormones may enhance radiation-induced apo- ptosis, prolonging suppression of tumor growth, agents have been studied both as single agents or may have a direct effect on tumor cells in and in combination, appreciable rates of objective patients in whom radiation failed [50,42]. Early radiologic and PSA responses are 20% to 50%.
studies found a benefit in disease-free survival, but Additionally, despite observations that chemo- not in overall survival, with radiation plus either therapy improves quality of life in men with orchiectomy or DES when compared with radia- hormone-resistant prostate cancer [70–72], no tion alone [44,45], although the lack of benefit in agent or regimen has yet demonstrated a survival overall survival with DES was probably caused by advantage in randomized clinical trials.
A study in 1998 by Eulau et al [50] evaluated 105 men treated with radiation therapy for locally advanced prostate cancer following radical prosta-tectomy. Twenty-nine evaluable patients under- There is compelling evidence that early hor- went androgen deprivation therapy (median 6 monal therapy prolongs life in many stages of months, range 2–10 months) combined with ra- prostate cancer. Large-scale trials to answer this diation therapy. Although there were 4 local question have not yet been conducted in surgically recurrences following therapy, none were seen in treated patients or in patients with PSA-only the men given hormone therapy. Both freedom relapse. Thus, many physicians and patients use from clinically evident distant relapse (p=0.014) early hormone therapy in PSA-only relapse. Many and freedom from biochemical relapse (p=0.004) unique new agents are being tested in this pop- were significantly superior in patients treated with ulation and may offer benefits. Patients and combination therapy, although no differences in physicians are encouraged to participate in such N.B. Davis et al / Urol Clin N Am 30 (2003) 403–414 trials, with hormone therapy reserved for sub- [13] Ornstein DK, Oh J, Herschman JD, et al. Evalu- ation and management of the man who has failed Following failure of primary hormone therapy, primary curative therapy for prostate cancer. Urol a standard algorithm of care exists: antiandrogen [14] Morris MM, Dallow KC, Zietman AL, et al.
withdrawal, use of alternative or first-line anti- Adjuvant and salvage irradiation following radical androgens, ketoconazole, and chemotherapy. At prostatectomy for prostate cancer. Int J Radiat each interval, clinical trials should be offered since none of these maneuvers are proven to prolong life.
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